Abstract Background Upadacitinib (UPA), a selective JAK1 inhibitor, has shown efficacy in clinical trials for moderate-to-severe ulcerative colitis (UC), but real-world data remain limited, particularly on outcomes related to prior exposure to other JAK inhibitors, such as tofacitinib (TOFA). This study evaluates real-world outcomes of UPA induction therapy in UC, focusing on clinical remission and differences by prior TOFA exposure. Methods This retrospective, observational study was conducted at a tertiary care centre in Spain, including adult patients with moderate-to-severe UC who initiated UPA in routine clinical practice. Data were retrospectively collected from electronic records, capturing baseline characteristics, TOFA exposure, disease duration, and concomitant treatments. The primary outcome was clinical remission at end of induction, assessed via the Physician Global Assessment (PGA) based on symptoms and laboratory data. Secondary outcomes included changes in faecal biomarkers, adverse events, treatment discontinuation, and maintenance dosing. Results Twenty-six patients were included, with a mean age of 50.5 years, 61.5% female, and a median disease duration of 10 years. All patients had prior exposure to advanced therapies, with 53.8% treated with at least three different lines of therapy. TOFA-exposed patients had a higher rate of pancolitis (84.6% vs. 30.8%; p=0.013), though endoscopic severity was similar between groups. All patients began with 45 mg UPA once daily; 23% had concomitant treatments, including vedolizumab (n=1), apheresis (n=3), and prednisone tapering (n=2). Following induction, 65.4% achieved clinical remission and 88.5% at least a partial response based on PGA. Among TOFA-naïve patients, 76.9% achieved remission and 100% partial response, compared to 53.8% and 76.9%, respectively, in TOFA-exposed patients (p=0.9). Faecal calprotectin levels decreased, with reductions of 96.7% in TOFA-naïve patients (from median 4002 µg/g to 132 µg/g) and 97.9% in TOFA-exposed patients (from 3556 µg/g to 76 µg/g). Extended induction was needed in 38.4% of patients, with no difference based on prior TOFA exposure (46.2% vs. 30.8%, p=0.6). Discontinuation during induction occurred in 23%, due to lack of effectiveness in 50%, adverse events in 33%, and transition to vedolizumab monotherapy in 17%. Post-induction, 88.4% continued on 30 mg as maintenance, consistent across both groups. Conclusion UPA induction therapy shows promise in achieving clinical remission in moderate-to-severe UC, with comparable outcomes independent of prior TOFA exposure. Our data suggests UPA may be a valuable option in real-world, treatment-experienced UC populations. Further studies could help clarify its role in complex cases and refine treatment strategies
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